Estrogen and glucocorticoid receptors co-regulate acrolein-induced respiratory and systemic homeostatic stress responses

The contribution of neuroendocrine mechanisms of air pollution health effects in females and the extent to which such effects are related to estrogen signaling are unclear. To examine the interactive roles of estrogen (ER) and glucocorticoid receptors (GR) in acrolein-induced respiratory and systemic effects, female Wistar-Kyoto rats were treated daily for 9-days with corn oil (vehicle, 1-mL/kg), fulvestrant (ER-antagonist/degrader, 20 mg/kg), mifepristone (GR antagonist, 30 mg/kg) or fulvestrant+mifepristone, and on day-8 and -9 post-drug-treatment, rats were exposed nose-only to 0 or 3.2 ppm acrolein for ~4hours/day. Glucose-tolerance testing was performed following the first exposure. Nasal and lung lavages and blood samples were collected following second exposure. Fulvestrant and mifepristone pretreatments decreased serum estrogen and progesterone, respectively, and each drug increased adrenocorticotropic hormone in acrolein-exposed rats. Although acrolein-induced nasal and lung protein leakage was reduced in fulvestrant-treated rats, neutrophilic inflammation and pro-inflammatory cytokines increases were exacerbated. However, acrolein-induced airway inflammation was not observed in mifepristone or co-treated rats. Regarding systemic markers of HPA activity, fulvestrant and mifepristone each increased circulating basal leukocytes regardless of exposure, especially total white blood cells and neutrophils. Fulvestrant-induced neutrophilia was slightly dampened in acrolein-exposed females. Fulvestrant also primed multiple adverse acrolein-induced metabolic alterations. Importantly, systemic markers of acrolein-induced HPA activity were not impacted in mifepristone or fulvestrant+mifepristone co-treated rats. These data demonstrate acrolein-induced respiratory and systemic stress effects are exacerbated by inhibiting ER, whereas GR antagonism selectively modulated ER influence. Thus, neuroendocrine co-regulation of ER and GR might explain acrolein susceptibility differences.

Impact/Purpose

Although the host response to environmental exposures, including air pollutants, is notably influenced by sex, underlying mechanisms contributing to sex-linked variations are not entirely clear. These results of this study highlight the interactive roles of steroid estrogen and glucocorticoid signaling pathways and the integrated influence of hypothalmus pituitary adrenal and hypothalamus pituitary gonadal axes in acrolein-induced respiratory and systemic stress effects and likely have broader applications to the understanding of mechanisms of sex-specific air pollution health outcomes. Numerous human reports have already connected sex hormone influence with lung function and inflammatory disease outcomes, suggesting sex hormones and their receptors as modulators of airway and even systemic reactions following environmental exposures. As neuroendocrine regulation of air pollutant-related health effects is becoming increasingly recognized in explaining human susceptibility, the results in the present study contribute to the understanding of sex differences in air pollution health effects that involve neurohormonal mechanisms. Further understanding the complex roles of sex hormone signaling pathways in stress may help elucidate sex-specific therapeutic targets.  

Citation

Alewel, D., K. Rentschler, M. Schladweiler, C. Miller, S. Gavett, P. Evansky, R. Grindstaff, W. Williams, AND U. Kodavanti. Estrogen and glucocorticoid receptors co-regulate acrolein-induced respiratory and systemic homeostatic stress responses. Society of Toxicology, RESTON, VAkfaf084, (2025). [DOI: 10.1093/toxsci/kfaf084]

DOI: Estrogen and glucocorticoid receptors co-regulate acrolein-induced respiratory and systemic homeostatic stress responses